How Emergency Medicine Residents Have Conversations About Life-Sustaining Treatments in Critical Illness: A Qualitative Study Using Inductive Thematic Analysis.

STUDY OBJECTIVE: The inherent pressures of high-acuity, critical illness in the emergency department create a unique environment whereby acute goals-of-care discussions must be had with patients or substitute decision makers to rapidly decide between divergent treatment paths. Among university-affiliated hospitals, resident physicians are often conducting these highly consequential discussions. This study aimed to use qualitative methods to explore how emergency medicine residents make recommendations regarding life-sustaining treatments during acute goals-of-care discussions in critical illness. METHODS: Using qualitative methods, semistructured interviews were conducted with a purposive sample of emergency medicine residents in Canada from August to December 2021. Inductive thematic analysis of the interview transcripts was conducted using line-by-line coding, and key themes were identified through comparative analysis. Data collection continued until thematic saturation was reached. RESULTS: Seventeen emergency medicine residents from 9 Canadian universities were interviewed. Two factors guided residents' treatment recommendations (a duty to provide a recommendation and the balance between disease prognosis and patient values). Three factors influenced residents' comfort when making recommendations (time constraints, uncertainty, and moral distress). CONCLUSION: While conducting acute goals-of-care discussions with critically ill patients or their substitute decision makers in the emergency department, residents felt a sense of duty to provide a recommendation informed by an intersection between the patient's disease prognosis and the patient's values. Their comfort in making these recommendations was limited by time constraints, uncertainty, and moral distress. These factors are important for informing future educational strategies.

Impact of baseline beta-blocker use on inotrope response and clinical outcomes in cardiogenic shock: a subgroup analysis of the DOREMI trial.

BACKGROUND: Cardiogenic shock (CS) is associated with significant morbidity and mortality. The impact of beta-blocker (BB) use on patients who develop CS remains unknown. We sought to evaluate the clinical outcomes and hemodynamic response profiles in patients treated with BB in the 24 h prior to the development of CS. METHODS: Patients with CS enrolled in the DObutamine compaREd to MIlrinone trial were analyzed. The primary outcome was a composite of all-cause mortality, resuscitated cardiac arrest, need for cardiac transplant or mechanical circulatory support, non-fatal myocardial infarction, transient ischemic attack or stroke, or initiation of renal replacement therapy. Secondary outcomes included the individual components of the primary composite and hemodynamic response profiles derived from pulmonary artery catheters. RESULTS: Among 192 participants, 93 patients (48%) had received BB therapy. The primary outcome occurred in 47 patients (51%) in the BB group and in 52 (53%) in the no BB group (RR 0.96; 95% CI 0.73-1.27; P = 0.78) throughout the in-hospital period. There were fewer early deaths in the BB group (RR 0.41; 95% CI 0.18-0.95; P = 0.03). There were no differences in other individual components of the primary outcome or in hemodynamic response between the two groups throughout the remainder of the hospitalization. CONCLUSIONS: BB therapy in the 24 h preceding the development of CS did not negatively influence clinical outcomes or hemodynamic parameters. On the contrary, BB use was associated with fewer deaths in the early resuscitation period, suggesting a paradoxically protective effect in patients with CS. Trial registration ClinicalTrials.gov Identifier: NCT03207165.

Cost of Futile ICU Care in One Ontario Hospital.

Critical care is a costly and finite resource that provides the ability to manage patients with life-threatening illnesses in the most advanced forms available. However, not every condition benefits from critical care. There are unrecoverable health states in which it should not be used to perpetuate. Such situations are considered futile. The determination of medical futility remains controversial. In this study we describe the length of stay (LOS), cost, and long-term outcomes of 12 cases considered futile and that have been or were considered for adjudication by Ontario's Consent and Capacity Board (CBB). A chart review was undertaken to identify patients admitted to the Intensive Care Unit (ICU), whose care was deemed futile and cases were considered for, or brought before the CCB. Costs for each of these admissions were determined using the case-costing system of The Ottawa Hospital Data Warehouse. All 12 patients identified had a LOS of greater than 4 months (range: 122-704 days) and a median age 83.5 years. Seven patients died in hospital, while 5 were transferred to long term or acute care facilities. All patients ultimately died without returning to independent living situations. The total cost of care for these 12 patients was $7 897 557.85 (mean: $658 129.82). There is a significant economic cost of providing resource-intensive critical care to patients in which these treatments are considered futile. Clinicians should carefully consider the allocation of finite critical care resources in order to utilize them in a way that most benefits patients.

Survey on Barriers to Critical Care and Palliative Care Integration.

PURPOSE: It has been shown that integrating palliative care (PC) in intensive care unit (ICU) improves end-of-life care (EOLC), but very few Canadian hospitals have adopted this practice. Our study aims to evaluate the perceived quality of EOLC at participating institutions and explore barriers toward ICU-PC integration. MATERIALS AND METHODS: A self-administered questionnaire was developed by a multidisciplinary team. Survey items were extracted from published quality indicators in EOLC and barriers to ICU-PC integration. The study took place at 2 academic institutions. Participants consisted of physicians and nurses, ICU administrators, and allied health workers. RESULTS: An overall response of 45% was achieved. Of total, 85% of the respondents were ICU nurses. The following main themes were identified: (1) There is a poor presence of PC in the ICU and 78% of respondents felt that increasing ICU-PC integration will improve quality of EOLC; (2) the main barrier to integration was unrealistic patient and/or family expectations; and (3) criteria-triggered consultation to PC was the most feasible way to achieve integration. CONCLUSION: Our findings indicate that the majority of respondents perceive that the presence of PC in ICU will improve EOLC. Future quality improvement initiatives can focus on developing a set of criteria for triggering PC consults.

An Analysis of Pay-for-Performance Schemes and Their Potential Impacts on Health Systems and Outcomes for Patients.

Pay-for-performance (P4P) programs have been introduced into the Canadian medical system in the last decades. This paper examines the underlying characteristics of P4P and describes both their advantages and drawbacks. Most P4P programs provide the advantage of rewarding medical acts, thus providing an incentive to take on complex patients. There is a variety of nuanced P4P initiatives, which provide financial incentive according to differing criteria, based on quality measures, incentives, and/or benchmark structures. However, there is no conclusive evidence demonstrating that P4P programs provide better value for money than traditional pay schemes, regardless of particular structural choices. Some evidence has even shown that P4P may be detrimental, especially in disadvantaged and high-risk populations. Additionally, there are a number of ethical and practical concerns that arise with the use of P4P, such as the risk of financial incentives being misused or misinterpreted and patients being refused or referred during treatment. P4P initiatives require careful examination and the creation of solid, evidence-based criteria for evaluation and implementation in Canadian medical systems.

Outcomes and Cost of Patients With Terminal Cancer Admitted to Acute Care in the Final 2 Weeks of Life: A Retrospective Chart Review.

BACKGROUND: Patients with terminal conditions are often admitted to the emergency department (ED) for acute medical services, but studies have suggested that multiple ED admissions may negatively impact end-of-life (EOL) care. Research have shown that incorporating palliative care (PC) is integral to optimal EOL care, but it is an aspect of medical practice that is often neglected. The current study sought to provide an overview of health outcomes and hospital costs of patients with cancer admitted to The Ottawa Hospital and/or received acute medical services during their final 2 weeks of life. Cost comparisons and estimates were made between hospital and hospice expenditures. METHODS: We conducted a retrospective chart review of palliative patients who died at The Ottawa Hospital in 2012. A total of 130 patients who visited the ED within 2 weeks of death were included in the analyses. RESULTS: In this cohort of patients, 71% of admitted patients did not have advanced care directives and 85% experienced a metastasis, but only 18% had a PC medical doctor. Patients were hospitalized, on average, for 7 days and hospitalization costs exceeded the estimated hospice cost by approximately 2.5 times (Can$1 041 170.00 at Can$8009.00/patient vs Can$401 570.00 at Can$3089.00/patient, respectively). CONCLUSION: Our study highlighted the importance of PC integration in high-risk patients, such as those in oncology. Patients in our sample had minimal PC involvement, low advanced care directives, and accrued high costs. Based on our analyses, we concluded that these patients would have likely benefited more from hospice care rather than hospitalization.

Ethical failings of CPSO policy and the health care consent act: case review.

End-of-life disputes in Ontario are currently overwhelmingly assessed through the singular lens of patient autonomy. The current dispute resolution mechanism(s) does not adequately consider evidence-based medical guidelines, standards of care, the patient's best interests, expert opinion, or distributive justice. We discuss two cases adjudicated by the Consent and Capacity board of Ontario that demonstrate the over emphasis on patient autonomy. Current health care policy and the Health Care Consent Act also place emphasis on patient autonomy without considering other ethically defensible factors. We argue that current policy and legislation require amendment, and unless there are measures undertaken to modify them, both the quality of care provided and the long-term capabilities of the health care system to remain publicly-funded, comprehensive and equitable, are at stake.

Neuroscience Intermediate-Level Care Units Staffed by Intensivists: Clinical Outcomes and Cost Analysis.

INTRODUCTION:: With an aging population and increasing numbers of intensive care unit admissions, novel ways of providing quality care at reduced cost are required. Closed neurointensive care units improve outcomes for patients with critical neurological conditions, including decreased mortality and length of stay (LOS). Small studies have demonstrated the safety of intermediate-level units for selected patient populations. However, few studies analyze both cost and safety outcomes of these units. This retrospective study assessed clinical and cost-related outcomes in an intermediate-level neurosciences acute care unit (NACU) before and after the addition of an intensivist to the unit's care team. METHODS:: Starting in October 2011, an intensivist-led model was adopted in a 16-bed NACU unit, including daytime coverage by a dedicated intensivist. Data were obtained from all patients admitted 1 year prior to and 2 years after this intervention. Primary outcomes were LOS and hospital costs. Safety outcomes included mortality and readmissions. Descriptive and analytic statistics were calculated. Individual and total patient costs were calculated based on per-day NACU and ward cost estimates and significance measured using bootstrapping. RESULTS:: A total of 2931 patients were included over the study period. Patients were on average 59.5 years and 53% male. The most common reasons for admission were central nervous system (CNS) tumor (27.6%), ischemic stroke (27%), and subarachnoid hemorrhage (11%). Following the introduction of an intensivist, there was a significant reduction in NACU and hospital LOS, by 1 day and 3 days, respectively. There were no differences in readmissions or mortality. Adding an intensivist produced an individual cost savings of US$963 in NACU and US$2687 per patient total hospital stay. CONCLUSION:: An intensivist-led model of intermediate-level neurointensive care staffed by intensivists is safe, decreases LOS, and produces cost savings in a system increasingly strained to provide quality neurocritical care.

Defibrillator Design and Usability May Be Impeding Timely Defibrillation.

BACKGROUND: Timely defibrillation is the only rhythm-specific therapy proven to increase survival to hospital discharge following cardiac arrest secondary to ventricular tachyarrhythmia. Delayed defibrillation occurs in more than 30% of this population. A study was conducted to test the hypothesis that unintuitive defibrillator design and lack of usability are barriers to timely defibrillation, as measured by time to defibrillation and the proportion of defibrillations delivered within 2 minutes. METHODS: A mixed-methods (qualitative and quantitative) prospective usability study was performed to evaluate the use of a defibrillator in a simulated hospital environment. Participants were asked to perform two simulated tasks typical of in-hospital cardiac arrest care: defibrillation and synchronized cardioversion. RESULTS: The average time to defibrillation was 4 minutes 21 seconds. Only 9.1% of participants (2/22) performed a defibrillation within 2 minutes. Participants had difficulty with several aspects of defibrillator use, including attaching the hands-free defibrillator electrode pads and selecting an appropriate display. Participants rated defibrillator design 4.2 ± 1.8 (mean, standard deviation) on a perceived usability scale (1 = "poorly designed"; 9 = "perfectly designed"). CONCLUSION: Most participants were unable to perform a simulated defibrillation within 2 minutes. This delay in defibrillation was likely at least partially the result of poor defibrillator design and lack of usability. Expert observation and participant feedback were largely congruent in terms of which aspects of defibrillator design do not suit the end user. Modification of future defibrillator design, along with improved education and training, may result in more timely defibrillation.

The impact of reducing intensive care unit length of stay on hospital costs: evidence from a tertiary care hospital in Canada.

PURPOSE: To use theoretical modelling exercises to determine the effect of reduced intensive care unit (ICU) length of stay (LOS) on total hospital costs at a Canadian centre. METHODS: We conducted a retrospective cost analysis from the perspective of one tertiary teaching hospital in Canada. Cost, demographic, clinical, and LOS data were retrieved through case-costing, patient registry, and hospital abstract systems of The Ottawa Hospital Data Warehouse for all new in-patient ward (30,483) and ICU (2,239) encounters between April 2012 and March 2013. Aggregate mean daily variable direct (VD) costs for ICU vs ward encounters were summarized by admission day number, LOS, and cost centre. RESULTS: The mean daily VD cost per ICU patient was $2,472 (CAD), accounting for 67.0% of total daily ICU costs per patient and $717 for patients admitted to the ward. Variable direct cost is greatest on the first day of ICU admission ($3,708), and then decreases by 39.8% to plateau by the fifth day of admission. Reducing LOS among patients with ICU stays ≥ four days could potentially result in an annual hospital cost saving of $852,146 which represents 0.3% of total in-patient hospital costs and 1.2% of ICU costs. CONCLUSION: Reducing ICU LOS has limited cost-saving potential given that ICU costs are greatest early in the course of admission, and this study does not support the notion of reducing ICU LOS as a sole cost-saving strategy.

The Impact of Palliative Care Consultation in the ICU on Length of Stay: A Systematic Review and Cost Evaluation.

INTRODUCTION: The intensive care unit (ICU) consumes 20% of hospital expenditures and 1% of gross domestic product. Many strategies have been attempted to reduce ICU costs. A systematic review was conducted to evaluate the effect of palliative care (PC) consultations in the ICU on length of stay (LOS) and costs. METHODS: A literature search was performed using PubMed, MEDLINE, EMBASE, and the Cochrane Library. Randomized controlled trials (RCTs), prospective, and retrospective cohort studies looking at PC consultations in adult ICUs published between January 2000 and February 2016 were selected. Independent reviewers assessed the eligibility of studies, extracted data on ICU, hospital LOS, and mortality, and rated each study's quality. The cost was derived from an existing model in the literature; the primary outcome was ICU LOS and the secondary outcomes were direct variable costs, mortality, and hospital LOS. RESULTS: We reviewed 814 abstracts, but only 8 studies met inclusion criteria and were included. The patients with a PC consultation in the ICU, when compared to those who did not, showed a trend toward reduced LOS. This reduction was statistically significant in the higher quality studies. Mortality was similar in both groups. Palliative care consultations also lead to a reduction in costs in 5 of the 8 eligible trials. On average, ICU costs were USD7533 and USD6406 (control vs PC, P < .05) and hospital direct variable costs were USD9518 and USD8971 ( P < .05) per admission. Due to interstudy heterogeneity, all outcomes were described narratively. CONCLUSION: This review demonstrates a trend that PC consultations reduce LOS and costs without impacting mortality. However, due to the small sample sizes and varying degrees of quality of evidence, many questions remain. A large multicenter RCT and formal economic evaluation would be needed for more definitive results.

Critical care at the end of life: a population-level cohort study of cost and outcomes.

BACKGROUND: Despite the high cost associated with ICU use at the end of life, very little is known at a population level about the characteristics of users and their end of life experience. In this study, our goal was to characterize decedents who received intensive care near the end of life and examine their overall health care use prior to death. METHODS: This was a retrospective cohort study that examined all deaths in a 3-year period from April 2010 to March 2013 in Ontario, Canada. Using population-based health administrative databases, we examined healthcare use and cost in the last year of life. RESULTS: There were 264,754 individuals included in the study, of whom 18% used the ICU in the last 90 days of life; 34.5% of these ICU users were older than 80 years of age and 53.0% had more than five chronic conditions. The average cost of stay for these decedents was CA$15,511 to CA$25,526 greater than for those who were not admitted to the ICU. These individuals also died more frequently in hospital (88.7% vs 36.2%), and spent more time in acute-care settings (18.7 days vs. 10.5 days). CONCLUSIONS: We showed at a population level that a significant proportion of those with ICU use close to death are older, multi-morbid individuals who incur significantly greater costs and die largely in hospital, with higher rates of readmission, longer lengths of stay and higher rates of aggressive care.

Cost analysis of the very elderly admitted to intensive care units.

BACKGROUND: Very elderly patients are often admitted to intensive care units (ICUs) despite poor outcomes and frequent preference to avoid unnecessary prolongation of life. We sought to determine the cost of ICU admission for the very elderly and the factors influencing this cost. METHODS: This prospective, observational cohort study included patients ≥80 years old admitted to 22 Canadian ICUs from 2009 to 2013. A subset of consenting individuals comprised a longitudinal cohort followed over 12 months. Costs were calculated from ICU length of stay and unit costs for ICU admission from a Canadian academic hospital. A generalized linear model was employed to identify cost-predictive variables. RESULTS: In total, 1671 patients were included; 610 were enrolled in the longitudinal cohort. The average age was 85 years; median ICU length of stay was 4 days. Mortality was 35% (585/1671) in hospital and 41% (253/610) at 12 months. The average cost of ICU admission per patient was $31,679 ± 65,867. Estimated ICU costs were $48,744 per survivor to discharge and $61,783 per survivor at 1 year. For both decedents and survivors, preference for comfort measures over life support was an independent predictor for lower cost (P < 0.01). CONCLUSIONS: Considering the poor clinical outcomes, and that many ICU admissions may be undesired by very elderly patients, ICU costs in this population are substantial. Our finding that a preference for comfort care predicted a lower cost independent of mortality reinforces the importance of early goals of care discussions to avoid both undesired and potentially non-beneficial interventions, consequently reducing costs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01293708 . Registered on 10 February 2011.

Compartment Syndrome as a Result of Systemic Capillary Leak Syndrome.

Objective. To describe a single case of Systemic Capillary Leak Syndrome (SCLS) with a rare complication of compartment syndrome. Patient. Our patient is a 57-year-old male, referred to our hospital due to polycythemia (hemoglobin (Hgb) of 220 g/L), hypotension, acute renal failure, and bilateral calf pain. Measurements and Main Results. The patient required bilateral forearm, thigh, and calf fasciotomies during his ICU stay and continuous renal replacement therapy was instituted following onset of acute renal failure and oliguria. Ongoing hemodynamic (Norepinephrine and Milrinone infusion) and respiratory (ventilator) support in the ICU was provided until resolution of intravascular fluid extravasation. Conclusions. SCLS is an extremely rare disorder characterized by unexplained episodic capillary hyperpermeability, which causes shift of volume and protein from the intravascular space to the interstitial space. Patients present with significant hypotension, hemoconcentration, hypovolemia, and oliguria. Severe edema results from leakage of fluid and proteins into tissue. The most important part of treatment is maintaining stable hemodynamics, ruling out other causes of shock and diligent monitoring for complications. Awareness of the clinical syndrome with the rare complication of compartment syndrome may help guide investigations and diagnoses of these critically ill patients.

Approach to economic analysis in critical care.

There are 4 general economic analyses used in health care: cost minimization, cost-benefit, cost-effectiveness, and cost utility. In this review, we provide an overview of each of these analyses and examine their appropriateness and effectiveness in assessing critical care costs. In the intensive care unit setting, it is particularly important to consider the patients' quality of life following the treatment of critical illness and to adopt a societal perspective when conducting economic analyses. Therefore, of the 4 economic analyses we cover, we recommend the use of cost-effectiveness and cost utility analyses.

Effectiveness of an extended period of flashing lights and strategic signage to increase the salience of alcohol-gel dispensers for improving hand hygiene compliance.

BACKGROUND: Multiple factors affect compliance with hand hygiene, including conspicuity of alcohol-gel dispensers. Previous studies have shown that flashing lights increase hand hygiene compliance; however, the durability of this effect has not been studied. METHODS: We affixed flashing lights to hand sanitizer dispensers for a total of 6 weeks. Regression analysis was used to compare compliance rates between the beginning and end of the intervention. Our secondary objective was to determine whether compliance rates in cold weather could be improved by adding a sign separated in time and space from the dispensers. RESULTS: Flashing lights improved hand hygiene compliance from 11.8% to 20.7%, and this effect was unchanged over the 6-week study period. Fully charged lights resulted in a greater compliance increase. A preemptive sign did not have a significant effect on hand hygiene rates nor did absolute temperatures. CONCLUSIONS: Flashing lights are a simple, inexpensive way of improving hand hygiene. Brighter lights appear to have a greater effect; however, this must be balanced with annoyance in specific settings. Temperature did not have a significant effect; however, this may be because the relationship does not fit a linear model. Other interventions, such as signs, may need to be tailored specifically to individual hospital environments.

A study of the efficacy of flashing lights to increase the salience of alcohol-gel dispensers for improving hand hygiene compliance.

BACKGROUND: Many interventions have been implemented to improve hand hygiene compliance, each with varying effects and monetary costs. Although some previous studies have addressed the issue of conspicuousness, we found only 1 study that considered improving hand hygiene by using flashing lights. METHOD: Our attention theory-based hypothesis tested whether a simple red light flashing at 2-3 Hz affixed to the alcohol gel dispensers, within the main hospital entrance, would increase hand hygiene compliance over the baseline rate. Baseline and intervention observations were completed over five 60-minute periods (Monday-Friday) from 7:30 to 8:30 AM using a covert observation method. RESULTS: Baseline hand hygiene compliance was 12.4%. Our intervention increased compliance to 23.5% during cold weather and 27.1% during warm weather. Overall, our pooled compliance rate increased to 25.3% (P < .0001). CONCLUSIONS: A simple, inexpensive flashing red light affixed to alcohol gel dispensers was sufficiently salient to approximately double overall hand hygiene compliance within the main hospital entrance. We hypothesize that our intervention drew attention to the dispensers, which then reminded employees and visitors alike to wash their hands. Compliance was worse during cold days, presumably related to more individuals wearing gloves.

Increasing benefit from revascularization is associated with increasing amounts of myocardial hibernation: a substudy of the PARR-2 trial.

OBJECTIVES: We sought to determine: 1) whether F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) parameters identify high-risk patients who gain benefit from revascularization; 2) whether there is a cut point for such benefit; and 3) predictors of outcome in patients with severe left ventricular (LV) dysfunction due to coronary artery disease. BACKGROUND: Patients with ischemic LV dysfunction might benefit from revascularization but not without risk. The FDG PET imaging can detect viable myocardium that recovers after revascularization. In the PARR-2 (PET and Recovery Following Revascularization-2) trial, FDG PET imaging showed a nonsignificant trend for improved outcome compared with standard care. Understanding the predictors of outcome from this prospective trial should help better identify patients at risk and which patients most benefit from revascularization. METHODS: This post hoc analysis included 182 patients with left ventricular ejection fraction (LVEF) <35% and coronary artery disease, being considered for revascularization work-up, and randomized to the PET arm of PARR-2. The primary outcome was a composite of cardiac death, myocardial infarction, or cardiac repeat hospital stay at 1 year. RESULTS: There is an interaction between PET mismatch and protocol revascularization such that higher mismatch, when combined with revascularization, yields fewer primary outcome events (p = 0.02). On the basis of adjusted Cox modeling, with reduced mismatch (<7%), the risk is not significantly different with or without revascularization. As mismatch increases above this mark, risk is reduced with revascularization. Increasing creatinine (for a 10-mumol/l increase: hazard ratio: 1.03, 95% confidence interval: 1.01 to 1.06, p = 0.010) is also associated with increased risk, whereas decreasing LVEF (for a 2% decrease: hazard ratio: 1.08, 95% confidence interval: 0.99 to 1.18, p = 0.087) trends toward an association with increased risk. CONCLUSIONS: In this post hoc analysis, patients with ischemic cardiomyopathy with larger amounts of mismatch have improved outcome with revascularization. Renal function was also an independent predictor of outcome. The FDG PET seems to define high-risk patients that gain benefit from revascularization. (PET and Recovery Following Revascularization [PARR 2]; NCT00385242).

Pneumocystis jiroveci pneumonia prophylaxis is not required with a CD4+ T-cell count < 200 cells/microl when viral replication is suppressed.

OBJECTIVE: To determine the safety of discontinuing Pneumocystis jiroveci pneumonia (PCP) prophylaxis, in patients on effective antiretroviral therapy with CD4+ T-cell counts that have plateaued at < 200 cells/microl. METHODS: We prospectively evaluated a cohort of HIV infected patients at a multidisciplinary HIV clinic with sustained HIV RNA levels < 50 copies/ml and CD4+ T-cell counts that have plateaued at < 200 cells/microl and who have discontinued PCP prophylaxis. RESULTS: Nineteen patients fulfilled the above criteria. Eleven had been taking daily trimethoprim-sulfamethoxazole, seven were receiving monthly aerosolized pentamidine, and one patient never received any prophylaxis. The median CD4+ T-cell count at the time of discontinuation and at the most recent determination were 120 (range, 34-184) and 138 (range, 6-201) cells/microl, respectively. To date, patients have been off PCP prophylaxis for a mean of 13.7 +/- 10.6 months and a median of 9.0 (range 3-39) months for a total of 261 patient-months. To date, no patient has developed PCP. This is significantly different from the risk of developing PCP with a CD4+ T-cell count of < 200 cells/microl in untreated HIV infection (rate difference 9.2%; 95% confidence interval, 5.7 to 12.8%; P < 0.05). CONCLUSION: With sustained suppression of viral replication, PCP prophylaxis may not be necessary, regardless of CD4+ T-cell count. This illustrates a degree of immune recovery that occurs with virologic suppression that is not reflected in absolute CD4+ T-cell count or percentage and suggests that guidelines for P. jiroveci pneumonia prophylaxis may need to be re-evaluated.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inflammatory stimuli up-regulate secretion of the soluble GM-CSF receptor in human monocytes: evidence for ectodomain shedding of the cell surface GM-CSF receptor alpha subunit.

Soluble GM-CSF receptor alpha subunit (sGMRalpha) is a soluble isoform of the GMRalpha that is believed to arise exclusively through alternative splicing of the GMRalpha gene product. The sGMRalpha mRNA is expressed in a variety of tissues, but it is not clear which cells are capable of secreting the protein. We show here that normal human monocytes, but not lymphocytes, constitutively secrete sGMRalpha. Stimulation of monocytes with GM-CSF, LPS, PMA, or A23187 rapidly up-regulates the secretion of sGMRalpha in a dose-dependent manner, demonstrating that secretion is also regulated. To determine whether sGMRalpha arose exclusively through alternative splicing of the GMRalpha gene product, or whether it could also be generated through ectodomain shedding of GMRalpha, we engineered a murine pro-B cell line (Ba/F3) to express exclusively the cDNA for cell surface GMRalpha (Ba/F3.GMRalpha). The Ba/F3.GMRalpha cell line, but not the parental Ba/F3 cell line, constitutively shed a sGMRalpha-like protein that bound specifically to GM-CSF, was equivalent in size to recombinant alternatively spliced sGMRalpha (60 kDa), and was recognized specifically by a mAb raised against the ectodomain of GMRalpha. Furthermore, a broad-spectrum metalloprotease inhibitor (BB94) reduced constitutive and PMA-, A23187-, and LPS-induced secretion of sGMRalpha by monocytes, suggesting that shedding of GMRalpha by monocytes may be mediated in part through the activity of metalloproteases. Taken together, these observations demonstrate that sGMRalpha is constitutively secreted by monocytes, that GM-CSF and inflammatory mediators up-regulate sGMRalpha secretion, and that sGMRalpha arises not only through alternative splicing but also through ectodomain shedding of cell surface GMRalpha.